Almost 15 million Americans regularly work alternate shifts, including evening, night, and rotating shifts. Shift work is integral to the modern work force, which spans all age and ethnic groups. Observational studies have consistently associated rotating shift work with increases in cancer risk, prompting the WHO in December 2007 to classify night shift work a probable carcinogen - the main operating mechanism being assumed circadian disruption by means of melatonin suppression. Based on results from the Nurses' Health Study II (NHS2), in March 2009, Denmark as the first country worldwide began paying monetary compensation to women who developed breast cancer after 20 or more years of night shift work. Because no definitive strategy currently exists to reduce the cancer risk associated with shift work-induced circadian disruption, determining what aspects of shift schedules are most detrimental to health is the next frontier in shift work and disease prevention. To date, no study has examined how specific aspects of shift schedules including length, frequency of rotation, and hours worked per week interact and relate to cancer risk. Moreover, whether there is an age range at which people are particularly vulnerable to the effects of circadian disruption also remains unclear. Future research would benefit from a clear and complete description of work schedules and their effects on human cancer risk. In 2009, we have added a battery of shift work questions to the main NHS2 questionnaire. We newly assess specific aspects of the nurses' work schedule including types of shift schedules and changes throughout their professional career. In addition, other factors of potential relevance to circadian disruption were assessed, including morningness-eveningness and sleep duration during each of the various life time periods. To evaluate the hypothesis that certain aspects of shift work schedules are more strongly associated with breast cancer risk than others, we will use both a cohort and cross-sectional study approach. We estimate 1,108 newly diagnosed cases of breast cancer between 2009 and 2013. We will use these cases, as well as prevalent cases to enhance the power of subanalyses, for an estimated total of 4,295 women with a diagnosis of breast cancer through 2013. Because mechanisms that link shift work to breast cancer risk are similar for other cancers, the findings from this proposal are likely to affect not only the risk of breast cancer but that of other cancers and men as well. We expect that the impact of our results will extend well beyond the specific aims we currently propose. Ultimately, as time progresses and nurses become older, this data and the newly added battery of shift work questions will lay the foundation for a comprehensive and unique study of shift work on the health needs of older workers. PUBLIC HEALTH RELEVANCE: In December 2007, the WHO classified night shift work as probably inducing cancer - the main operating mechanism being assumed the suppression of melatonin and consequences thereof. Because no definitive strategy currently exists to reduce the cancer risk associated with shift work- induced changes in the body that could lead to cancer risk, determining what specific aspects of the nurses' work schedule including types of shift schedules and changes throughout their professional career are most detrimental to cancer risk is the next frontier in shift work and disease prevention.